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The ion channel mechanisms of the subthreshold inward depolarizing currents in the VTA dopaminergic neurons and their roles in the depression-like behavior

ABSTRACT: The dopaminergic (DA) neurons in the ventral tegmental area (VTA) of middle brain play important role in emotion related behaviour, and the alteration of excitability of VTA DA neurons are believed to be the key determinants in behaviours of depression and drug addictions. The excitability of VTA DA neurons controls the release of DA in the projection fiber terminals thus controls the function of VTA DA neurons. After many years hard work, we begin to understand how the excitability of VTA DA neurons are regulated, but these achievements are far from satisfactory. Furthermore, with recent progress and realization that property of VTA DA neurons, against the classical view that VTA DA neurons are homogeneous population, are distinctly different, thus the accumulated limited knowledge on the mechanism of excitability modulation of VTA DA neurons is especially short of expectation. The most outstanding indications of the heterogeneity of VTA DA neurons are represented by the distinctly different electrophysiological properties among VTA DA neurons projecting to different brain regions. However the underlying mechanism is not clear. In this application we plan to investigate the underlying mechanism determining the distinct excitability of VTA DA neurons projecting to the cortical and the limbic regions of the brain by single cell RNA sequencing (scRNA-seq). The main focus of the study will be on the intrinsic ion channels and the related modulation mechanism of VTA DA neuron excitability. On the basis of this we will further study the mechanism which underlie alteration of excitability of VTA DA neurons in condition of depression state, and still further the related depression behaviour.

ORGANISM(S): Mus musculus

PROVIDER: GSE276319 | GEO | 2024/11/27

REPOSITORIES: GEO

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Project description:Implications for neuroprotection in Parkinson's disease Parkinson’s disease and its characteristic symptoms are thought to arise from the progressive degeneration of specific midbrain dopamine (DA) neurons. In humans, DA neurons of the substantia nigra (SN) and their projections to the striatum show selective vulnerability, while neighboring DA neurons of the ventral tegmental area (VTA) are relatively spared from degeneration. This pattern of cell loss is mimicked in humans, primates, and certain rodents by the neurotoxin MPTP. In this study, we aimed to test the hypothesis that there are factors in the VTA that are potentially neuroprotective against MPTP and that these factors change over time. We have found a differential transcriptional response within the cells of the SN and VTA to sustained exposure to a low dose of MPTP. Specifically, the VTA has increased expression of 148 genes as an early response to MPTP and 113 genes as a late response to MPTP toxicity. This response encompasses many areas of cellular function, including protein regulation (Phf6) and ion/metal regulation (PANK2, Car4). Notably, these responses were largely absent from the cells of the SN. Our data show a clear dynamic response in maintaining the homeostasis and viability of the neurons in the VTA that is lacking in the SN after neurotoxin challenge. We used microarrays to analyze the differential response of the substantia nigra (SN) and ventral tegmental area (VTA) to a chronic low dose of the neurotoxin MPTP. Transgenic hTH-GFP mice were treated with MPTP (4mg/kg) for either 2 or 10 days. Control mice were given an equal volume of saline for 10 days. Dopamine neurons from the substantia nigra and ventral tegmental areas of control and MPTP treated animals were laser captured. The RNA was isolated and processed for microarray hybridization. Each group had three biological replicates, for a total of 18 samples. Three each in the following: Control SN, Control VTA, 2 day MPTP SN, 2 day MPTP VTA, 10 day MPTP SN, 10 day MPTP VTA. Samples were log2 transformed and RMA normalized using Agilent Genespring 10.0 GX.

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The ion channel mechanisms of the subthreshold inward depolarizing currents in the VTA dopaminergic neurons and their roles in the depression-like behavior

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